CH645892A5 - CARBOSTYRIL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND ANTIHISTAMINICALLY ACTIVE AGENTS CONTAINING THESE COMPOUNDS. - Google Patents

Description

The invention relates to new carbostyril derivatives and their salts, processes for their preparation and agents having an antihistamine action which contain the carbostyril derivative as an active ingredient.

The invention relates to carbostyril derivatives and their acid addition salts, salts with basic compounds and their quaternary salts, which are defined in claim 1.

The carbostyril derivatives and their salts of the general formula (1) have excellent antihistamine effects and are suitable for antihistamines.

The invention therefore further provides agents having an antihistamine action which contain at least one carbostyril derivative or a salt thereof of the type described above as the active ingredient.

Extensive animal studies have shown that the carbostyril derivatives according to the invention have excellent anti-histamine effects with fewer side effects, e.g. a CNS depressant effect or a ß-adrenergic blocking effect.

In various medical and pharmaceutical publications, e.g. Goodman-Gilman's "Yakuri Sho" (Textbook of Pharmacology) (first volume) - "Yakubutsu Chiryo No Kiso To Rinsho" (Fundamental and Clinic of Pharmacotherapy), pages 781-835, published by HirokawaShoten Co. (1974)]; "Shin-Oyo Yakurigaku" (New Applied Pharmacology) by Hisoshi Uno, pages 307-319 [published by Nagai Shoten Co. (1970)]; "Shin-Yaku To Rinsho" (Journal of New Remedies & Clinic), B and 20, No. 11, pages 129-133 (1971); and “Kiso To Rinsho” (Laboratory and Clinic), volume 10, no. 10, pages 17-27 (1976), describe that in general antihistamines isolate the combined histamine-active compound, which in allergies by the antigen Antibody response is formed

do not inhibit, but inhibit the combination of a histamine-active compound with a histamine acceptor through competitive antagonism and thereby produce an antihistaminic effect. The antihistamine agents according to the invention are therefore suitable for the therapeutic and prophylactic treatment of various allergic diseases and symptoms which are caused by the combination of histamine and histamine acceptor. Examples include allergic symptoms in the respiratory tract, e.g. N. sneezing, runny nose, stinging of the eyes, nose and throat, hay fever, pollinosis, acute urticaria (itching, edema, inflammation and the like), vascular edema, pruritus, atopic dermatitis, insect bites, contact dermatitis, e.g. B. "urushi kabure" (ivy poisoning), urticaria and edema disorders in serum diseases, allergic rhinitis, allergic conjunctivitis or corneitis. Furthermore, the antihistamines according to the invention can also be used as a supplement in the treatment of systemic anaphylaxis, in which autacoids other than histamine can play an important role. Furthermore, the carbostyril derivatives according to the invention can also be used as diagnostics for determining gastric juice secretion.

Some carbostyril derivatives with useful pharmacological properties, e.g. anti-inflammatory effect,

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Inhibitory effects on platelet agglutination, CNS depressant and β-adrenergic blocking effects are known in the literature, e.g. from U.S. Patent No. 3,994,900,4147869; DE-OS No. 2302027 and 2711719; and JA-AS No. 106977/1975 and 142576/1975.

However, these references do not describe that these carbostyril derivatives have antihistamine effects.

On the other hand, other carbostyril derivatives with antihistamic effects are known from other publications, e.g. B. from DE-OS 2912105 and JA-ASen 16478 / 1979,2693 / 1980,89221 / 1980,89222 / 1980. These known carbostyril derivatives with antihistamine effects, however, differ from the carbostyril derivatives according to the invention with regard to the type and position of the substituents.

Furthermore, the carbostyril derivatives according to the invention have selective antihistamine effects, but less CNS-depressant activity and β-adrenergic nerve blocking effects in comparison to the known carbostyril derivatives.

Specific examples of groups R1, R2, R3, R4, X and Y of the general formula (1) are given below.

The term “lower alkenyl group” means a straight-chain or branched alkenyl group with 2 to 6 carbon atoms. Examples include the vinyl group, allyl group, 2-butenyl group, l-methyl-2-butenyl group, 2-pentenyl group, 2-hexenyl group and the like.

The term “lower alkynyl group” means a straight-chain or branched alkynyl group with 2 to 6 carbon atoms. Examples include the ethynyl group, propargyl group, 2-butynyl group, 1-methyl-2-propargyl group, 2-pentynyl group, 2-hexynyl group and the like.

The term "lower alkyl group which may have one or more phenyl groups as a substituted group (s)" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms which may have one or more phenyl groups as a substituted group (s). Examples include the methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, pentyl group, hexyl group, benzyl group, 1-phenylethyl group, 2-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group, l, l-dimethyl-2-phenylethyl group , 5-phenylpentyl group, 6-phenylhexyl group, diphenylmethyl group and the like ...

The term “lower alkyl group” means a straight-chain or branched alkyl group with 1 to 6 carbon atoms. Examples include the methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, pentyl group, hexyl group and the like.

The term “lower alkyl group with one or more phenyl groups as substituted group (s)” means a straight-chain or branched alkyl group with 1 to 6 carbon atoms, which has one or more phenyl groups as substituted group (s). Examples include the benzyl group, 1-phenyl group, 2-phenylethyl group, 3-phenylpropyl group,

4-phenylbutyl group, 1,1, -dimethyl-2-phenylethyl group,

5-phenylpentyl group, 6-phenylhexyl group, diphenylmethyl group and the like ...

The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term “lower alkoxy group” means a straight-chain or branched alkoxy group with 1 to 6 carbon atoms. Examples include the methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like ...

The term “lower alkanoyl group” means a straight-chain or branched alkanoyl group with 1 to 6 carbon atoms. Examples include the formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group,

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Pentanoyl group, tert-butylcarbonyl group, hexanoyl group and the like ...

The term "lower alkylene group means one or more hydroxyl groups as a substituted group (s)" means a straight-chain or branched alkylene group with 1 to 6 carbon atoms, which may have one or more hydroxyl groups as a substituted group (s). Examples include the methylene group, ethylene group, tri-methylene group, 2-methyltrimethylene group, 1-methyltrimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, 2-ethylethylene group, 2,2-dimethyltri-methylene group, 2-hydroxytrimethylene group, 2-hydroxy-tetramethylene group, 2,3-dihydroxytetramethylene group,

3-hydroxypentamethylene group and the like ...

Typical carbostyril derivatives of the general formula (1) are given below by way of example as follows. The term "3,4-dehydro compound" that appears at the end of the name of each compound means that it is a compound with a double bond between the 3 and

4-position in the carbostyril skeleton.

5- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [2-hydroxy-3 - (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-7- [2-hydroxy-3- (4-phenyl-l-piperidyl) -propoxy] -3,4-dihydrocarbostyriI and its 3,4-dehydro compound l-methyl-8- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-allyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l- Allyl-7- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5- [2-hydroxy-3 - (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 1- (4-phenylbutyl) -6- [2-hydroxy-3- (4-phenyl- l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-7- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro verb indung l-propargyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-propargyl-7- [2- hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 6-chloro-5- [2-hydroxy-3- (4-phenyl-l -piperidyl) -propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5-bromo-6- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-fluoro-7- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5-chloro-8- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6,8-dichloro-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-chloro-8-bromo-7- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5, 6-dibromo-8- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [2-Hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [2-Hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-benzyl-5- [2-hydroxy-3 - (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [2-Hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-methyl-5- [2-hydroxy-3 - (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-7- [2-hydroxy-3- (4-benzyl-l-piperidyl) -propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-propargyl-7- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-allyl-5- [2-hydroxy-3- (4-benzyI-l-piperidyI) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 8- Bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-6-chloro-7- [2 -hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-6,8-dichloro-5- [2-hydroxy-3 - (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarböstyril and its 3,4-dehydro compound l-allyl-6-chloro-7- [2-hydroxy-3- (4-benzyl- l-piperidyl) propoxy] -3,4-dihydrocarbostyril and se 3,4-dehydro compound

6,8-dibromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- {2-Hydroxy-3- [4- (2-phenylethyl) -l-piperidyl] propoxy \ -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-7 "{2-hydroxy -3- [4- (l-phenylethyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5 "j2-hydroxy-3- [4- ( 4-phenylethyl) -l-piperidyl] -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- (4-Benzyl-l-piperidylmethoxy) -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [2- (4-Benzyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2- (4-Benzyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [4- (4-Benzyl-l-piperidyl) butoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [5- (4-Benzyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [6- (4-Benzyl-l-piperidyl) hexyloxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [3- (4-benzyl-l-piperidyl) -propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-methyl-7- [3- (4-benzyl-l-piperidyl) -propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-hexyl-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-allyl- 5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-allyl-7- [3- (4-benzyl-l- piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound

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l- (l-methylallyl) -7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-propargyl-7- [3- ( 4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-propargyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3, 4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l- (phenylbutyl) -7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-7- [3- (4- benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound

5- {3- [4-phenylethyl) -l-piperidyl) propoxy} -3,4-dihydro-carbostyril and its 3,4-dehydro compound l- \ 3- [4- (2-phenylethyl) -l -piperidyl) -propoxy} - 3,4-dihydro-carbostyril and its 3,4-dehydro compound l-benzyl-5-j 3- [4- (2-phenylethyl) -l-piperidyl) -propoxy j- 3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-7-j 3- [4- (l-phenylethyl) -l-piperidyl) propoxy 3,4-dihydrocarbostyril and its 3,4-dehydro -Compound l-methyl-5-j 3- [4- (4-phenylbutyl) -l-piperidyl) propoxy \ -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-7-i 3 - [4- (6-phenylhexyl) -l-piperidyl) propoxy [• -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-bromo-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-methyl-5-bromo-6- [3 - (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-fluoro-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-benzyl-6-chloro-5- [3 - (4-benzyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5-chloro-8- [3- (4-benzyl-l-piperidyl) -propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-6-chloro-7- [3- (4-benzyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6,8-dichloro-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-chloro-8-bromo-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (4-Phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [3- (4-Phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [3- (4-Phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [3- (4-phenyl-l-piperidyl) -propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-benzyl-7- [3- (4-phenyl-l-piperidyl) -propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-benzyl-5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-methyl- 7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-propargyl-7- [3- (4-phenyl-l- piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-6-chloro-5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4- dihydrocarbostyril and its 3,4-dehydro compound

6,8-dichloro-5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-6,8-dichloro-5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-6-chloro-7- [3- (4-phenyl-l- piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-hexyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound

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1- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [2-Methyl-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Methyl-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2,2-Dimethyl-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [2-methyl-3 - (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-7- [2-methyl-3- (4-benzyl-l-piperidyl) -propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [2-methyl-4- (phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Methyl-4- (phenyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-methyl-5- [2-methyl-3- ( 4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 1-benzyl-7- [2-methyl-3- (4-phenyl-1-piperidyl) propoxy ] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-chloro-5- [2-methyl-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-methyl-6- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l, 4-dimethyl-5- [3- ( 4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy ] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-methyl-5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-methyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound 1,4-dimethyl-7- [3- ( 4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-7- [2-hydroxy -3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l, 4-dimethyl-5- [2-hydroxy-3- (4-benzyl- l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- (2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-phenyl-5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound l-benzyl-4-phenyl-7- [3 - (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-4-phenyl-5- [3- (4-phenyl-l-piperidyl) -propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-phenyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-phenyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-4-phenyl-7- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-phenyl-7- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-4-phenyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-chloro-7 - {3- [4- (2,3-dimethylphenyl) -l-piperidyl] propoxy} • -3,4-dihydrocarbostyril and its 3,4-dehydro compound

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5 "{3- [4- (2-fluorophenyl) -l-piperidyl] propoxy (-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-J 3- [4- (3-chlorophenyl) -l-piperidyl] propoxy} -3,4-dihydro-carbostyril and its 3,4-dehydro compound

6-j 3- [4- (4-chlorophenyl) -l-piperidyl] propoxy j-3,4-dihydro-carbostyril and its 3,4-dehydro compound

7-j 3- [4- (3,4-dichlorophenyl) -l-piperidyl] propoxy} ■ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (2-fluorophenyl) -l-piperidyl] propoxy [-3,4-dihydro-carbostyril and its 3,4-dehydro compound

5-j 3- [4- (2-Methylphenyl) -l-piperidyl] propoxy j-3,4-dihydro-carbostyril and its 3,4-dehydro compound

6-j 3- [4- (3-Ethylphenyl) -1-piperidyl] propoxy ^ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (4-Methylphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (2,3-Dimethylphenyl) -l-piperidyl] propoxy j - 3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4- (4-methoxyphenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (2-ethoxyphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4- (3-methoxyphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4- (3-methoxyphenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (3,4-dimethoxyphenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound 7-j 3- [4- (3,4 , 5-trimethoxyphenyl) -l-piperidyl] -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (2-chlorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4- (4-fluorophenyl) -l-piperidyl] propoxy [-3,4-dihydro-carbostyril and its 3,4-dehydro compound

5-j 3- [4- (3-MethylphenyI) -l-piperidyl] propoxy \ -3,4-dihydrocarbostyril and its 3,4-dehydro compound l- \ 3- [4- (2-methoxyphenyl ) -l-pipéridyl] -propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 2-Hydroxy-3- [4- (2-fluorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 2-Hydroxy-3- [4- (4-chlorophenyl) -l-piperidyl] propoxy} ~ 3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j2-Hydroxy-3- [4- (2-methoxyphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 2-Hydroxy-3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 2-Hydroxy-3- [4- (2-methylphenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7 - {2-Hydroxy-3- [4- (2,3-dimethylphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 2-hydroxy-3- [4- (3-methylphenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound 4-methyl-7-j 3- [ 4- (2-chlorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-Methyl-5-j 3- [4- (3-methoxyphenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-Methyl-7 "j2-hydroxy-3- [4- (2-methoxyphenyl) -1-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4- (2-fluorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4- (4-fluorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4- (3-Methylphenyl) -l-piperidyl] propoxy [-3,4-dihydro-carbostyril and its 3,4-dehydro compound

7-j 3- [4- (3-methoxyphenyl) -l-piperidyl] propoxy f-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 2-Hydroxy-3- [4- (2-fluorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7 - j2-Hydroxy-3- [4- (2-methoxyphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 2-Hydroxy-3- [4- (3-chlorophenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

4-phenyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [3- (l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [3- (l-allyl-2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [3- (l-benzyl-2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-ethylpiperidinium chloride

4-phenyl-l- [3- (l-propargyl-2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium chloride

4-phenyl-1- [3- (6-chloro-2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride

4- (2-fluorophenyl) -1- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -1-methylpiperidine chloride

4- (3-chlorophenyl) -1- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4- (3,4-dichlorophenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4- (2-methylphenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4- (4-methylphenyl) -1- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium chloride

4- (2,3-Dimethylphenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride

4- (4-Methoxyphenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium chloride

4- (2-methoxyphenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4- (3,4-Dimethoxyphenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4- (3,4,5-Trimethoxyphenyl) -l- [3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride

4-Benzyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4-Benzyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride

4-phenyl-1- [3- (2-oxo-1,2-dihydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4- (4-fluorophenyl) -1- [3- (2-oxo-1,2-dihydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4- (3-methylphenyl) -l- [3- (2-oxo-l, 2-dihydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4- (3-methoxyphenyl) -1- [3- (2-oxo-l, 2-dihydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4-Benzyl-l- [3- (2-oxo-l, 2-dihydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4-phenyl-l- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride

4-phenyl-l- [2-hydroxy-3- (l-methyl-2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [2-hydroxy-3- (l-benzyl-2-oxo-l, 2,3,4-tetrahydro-quinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4-phenyl-l- [2-hydroxy-3- (6-chloro-2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

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4-phenyl-l- [2-hydroxy-3- (6,8-dibromo-2-oxo-l, 2,3,4-tetra-hydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium- chloride 4- (2-fluorophenyl) -1- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-5-yl-oxy) propyl] -1-methylpiperidinium iodide

4- (2-methoxyphenyl) -l- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetra-hydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride 4 - (2,3-Dimethylphenyl) -l- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetra-hydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium chloride

4- (3-chlorophenyl) -1- [2-hydroxy-3- (2-oxo-1,2-dihydro-quinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4- (4-methoxyphenyl) -1- [2-hydroxy-3- (2-oxo-1,2-dihydro-quinolin-5-yl-oxy) propyl] -1-methylpiperidinium iodide

4- (2-Methylphenyl) -1- [2-hydroxy-3- (2-oxo-1,2-dihydro-quinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide

4-Hydroxy-4-phenyl-l- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetra-hydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide 4 -Acetyl-4-phenyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

4-Hydroxy-4-phenylrl- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetra-hydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

4-acetyl-4-phenyl-2- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -l-methylpiperidinium iodide

5- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4-Hydroxy-4- (4-chlorophenyl) -l-piperidyl] propoxy} ■ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- {3- [4-Hydroxy-4- (4-fluorophenyl) -l-piperidyl] propoxy j> -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-- | 3- [4-Hydroxy-4- (2-fluorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- {3- [4-Hydroxy-4- (2-chlorophenyl) -l-piperidyl] propoxy} • -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- {3- [4-Hydroxy-4- (3-chlorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4-Hydroxy-4- (4-bromophenyl) -l-piperidyl] propoxy} • -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5 "{3- [4-Hydroxy-4- (2,6-dichlorophenyl) -l-piperidyl] propoxy [--3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- {3- [4-Hydroxy-4- (3-fluorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- | 3- [4-Hydroxy-4- (3-bromophenyl) -l-piperidyl] propoxy \ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j 3- [4-hydroxy-4- (2-bromophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound 5-j 3- [4-hydroxy- 4- (4-iodophenyl) -l-piperidyl] -propoxy} ~ 3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (5-Phenyl-l, 5,7-triazaspiro [4.5] decan-8-one-l-yl) propoxy] - 3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [l- (4-Hydroxy-4-phenyl-l-piperidyl) methoxy] -3,4-dihydro-carbostyril and its 3,4-dehydro compound

5- [2- (4-Hydroxy-4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (4-Acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (4-Propionyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (4-Hexanoyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5- [2- (4-hydroxy- 4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [4- (4-Hydroxy-4-phenyl-l-piperidyl) butoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (4-chlorophenyl) -l-piperidyl] propoxy} ■ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

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6-j 3- [4-Hydroxy-4- (4-fluorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (2-fluorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (2-chlorophenyl) -l-piperidyl] propoxy} ■ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (3-chlorophenyl) -l-piperidyl] propoxy} • -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (4-bromophenyl) -l-piperidyl] propoxy} ■ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6 "j3- [4-Hydroxy-4- (2,6-dichlorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (3-fluorophenyl) -l-piperidyl] propoxy \ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-Hydroxy-4- (3-bromophenyl) -l-piperidyl] propoxy} ~ 3,4-dihydrocarbostyril and its 3,4-dehydro compound

6-j 3- [4-hydroxy-4- (2-bromophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound 6-j 3- [4-hydroxy- 4- (4-iodophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [3- (4-Acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [3- (4-Propionyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [3- (4-Hexanoyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (4-chlorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (4-fhiorphenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (2-fluorophenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (2-chlorophenyl) -l-piperidyl] propoxy \ -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (3-chlorophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (4-bromophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- [2- (4-Acetyl-4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (2,6-dichlorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (3-fluorophenyl) -l-piperidyl] propoxy | -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (3-bromophenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (2-bromophenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7-j 3- [4-Hydroxy-4- (4-iodophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (4-chlorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (4-fluorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (2-fluorophenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (2-chlorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (3-chlorophenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (4-bromophenyl) -l-piperidyl] propoxy} -3,4-dihydrocarbostyril and its 3,4-dehydro compound

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7- [3- (4-Acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [3- (4-Propionyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [3- (4-Hexanoyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyrene and its 3,4-dehydro compound

7- [2- (4-Hydroxy-4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [6- (4-Hydroxy-4-phenyl-l-piperidyl) hexyloxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j3- [4-Hydroxy-4- (2,6-dichlorophenyl) -l-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (3-fluorophenyl) -l-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-Hydroxy-4- (3-bromophenyl) -l-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8-j 3- [4-hydroxy-4- (2-bromophenyl) -l-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound 8-j 3- [4-hydroxy- 4- (4-iodophenyl) -l-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [3- (4-Acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [3- (4-Propionyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyrene and its 3,4-dehydro compound

8- [3- (4-Hexanoyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Hydroxy-3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

8- [2-Hydroxy-3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

5-j2-Hydroxy-3- [4-hydroxy- (4-chlorophenyl) -l-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5- [2- hydroxy-3- (4-hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

6- {2-Hydroxy-3- [4-acetyl-4- (3-methoxyphenyl) -1-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5 "j2-Hydroxy-3- [4-acetyl-4- (2,3-dimethylphenyl) -1-piperidyl] propoxy {-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [2-Hydroxy-3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -4-methyl-3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Hydroxy-3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -4-phenyl-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [2-Hydroxy-3- (4-hydroxy-4-phenyl-l-piperidyl) propoxy] -4-methyl-3,4-dihydrocarbostyril and its 3,4-dehydro compound

5- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -4-methyl-3,4-dihydrocarbostyril and its 3,4-dehydro compound 7- [3- (4-acetyl- 4-phenyl-l-piperidyl) propoxy] -4-phenyl-3,4-dihydrocarbostyril and its 3,4-dehydro compound 5- [2-hydroxy-3- (4-acetyl-4-phenyl-l- piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [2-hydroxy-3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] - 3,4-dihydrocarbostyril and its 3,4-dehydro compound l-benzyl-5- [2-hydroxy-3- (4-acetyI-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [2-hydroxy-3- (4-hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro -Connection

5- [3-Hydroxy-4- (4-acetyl-4-phenyM-piperidyl) butoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound

7- [2-Hydroxy-4- (4-hydroxy-4-phenyl-l-piperidyl) butoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 5 5-j 2-hydroxy-3- [4-hydroxy-4- (2,6-dichlorophenyl) -l-piperidyl] propoxyl-3,4-dihydrocarbostyril and its 3,4-dehydro compound l-methyl-5- [3- (4-hydroxy- 4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound 10 l-benzyl-7- [3- (4-acetyl-4-phenyl-l-piperidyl) - propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-allyl-5- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-propynyl-7- [3- (4-hydroxy-4-phenyl-l-piperidyl) propoxy] -15 3,4-dihydrocarbostyril and its 3,4-dehydro compound l- (4-phenylbutyl) -5- [3- (4-hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and its 3,4-dehydro compound l-butyl-7- [3 - (4-acetyl-4-phenyl-l-piperidyl) propoxy] -20 3,4-dihydrocarbostyril and its 3,4-dehydro compound l-crotyl-7- [3- (4-hydroxy-4-phenyl -l-piperidyl) -propoxy] -3,4-dihydrocarbo styril and its 3,4-dehydro compound.

According to the invention, the connections are made according to methods 25 to 29; these methods are illustrated below by Reaction Schemes 1, 4, 6, 7, 8 and 9.

30th

35

Reaction scheme 1

h, oc

(3)

40 wherein R1, R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the same meanings as defined above, and X1 represents a halogen atom.

The compound of the general formula (1) 45 is thus prepared by reacting a compound of the general formula (2) with a known piperidine derivative of the general formula (3). The reaction can be carried out in the absence or in the presence of an inert solvent at room temperature to about 200 ° C, preferably at a temperature in the range 50 from 60 to 120 ° C, for several hours to 24 hours.

There are no particular restrictions on the inert solvent. Any solvent that has no adverse effects and the reaction can be used. Examples include ethers such as dioxane, tetrahydrofuran (THF), ethylene glycol dimethyl ether, etc .; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; lower alcohols such as methanol, ethanol, isopropanol, etc.; and aprotic polar solvents such as dimethylform-60 amide (DMF), dimethyl sulfoxide (DMSO), etc. The reaction can advantageously be carried out using a basic compound as a dehydrohalogenating agent. There are no specific restrictions on the basic compound. Any basic 65 compounds can be used, e.g. Potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, tertiary amines such as triethylamine, tripropylamine, pyridine, quinoline or the like. Die

11

645 892

Reaction can also be carried out using an alkali metal salt, e.g. Potassium or sodium iodide as a reaction accelerator. The ratio of the amount of the compound of formula (2) to the amount of the compound of formula (3) in the above reaction is suitably such that the latter compound in an equimolar amount up to an excess amount, preferably an equimolar amount, up to 5 times the molar amount of the former compound, more preferably an equimolar amount up to 1.2 times the molar amount of the former compound is used.

The compounds of the general formula (2) which are used as starting materials in the reaction according to reaction scheme 1 include new compounds. These compounds can be prepared according to the following reaction schemes 2 and 3.

Reaction scheme 2

(6)

Halogeniortm #

25th

In it R1, R2, R4, X and the carbon-carbon bond between the 3 to 4 positions in the carbostyril skeleton have the meanings given above, and R5 stands for a lower alkyl group or a lower alkanoyl group, while n 'has the value 1 or has 2.

Reaction scheme 3

Oll II '

* X '- Y-X (9)

(8th)

In it, R1, R2, X, X1, Y, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the meanings given above, and X2 represents a halogen atom.

In the reaction according to the reaction scheme 2, a compound of the general formula (5) can be obtained by reacting a hydroxycarbostyril compound of the general formula (4) with a halogenating agent or by preparing a compound of the general formula (7) an alkoxy or alkanoyloxy-carbostyril compound of the general formula (6) hydrolyzed with a halogenating agent. The halogenation reaction can be carried out using known halogenating agents, e.g. of fluorine, chlorine, bromine, iodine, xenondi-fluoride, sulfuryl chloride, sodium hypochloride, hypochlorous acid, hypombromic acid, bleaching powder, iodine chloride or the like. The amount of halogenating agent can be suitably selected from a wide range according to the halogen atoms included in the Starting compound (4) or (6) are to be introduced. In the case of introducing 1 5 halogen atom, the halogenating agent is usually used in an equimolar or excess amount, preferably 1 to 1.5 times the molar amount of the starting compound. In the case of the introduction of 2 halogen atoms, the halogenating agent is used in a 2-fold molar amount up to a large excess, preferably in a 2-to 3-fold molar amount of the respective starting compounds. The halogenation reaction is usually carried out in a suitable solvent, e.g. B. water, methanol, ethanol, chloroform, carbon tetrachloride, acetic acid or a mixture thereof. The reaction temperature is not particularly limited, but the reaction is usually carried out at a temperature in the range from about -20 to about 100 ° C, preferably at 0 ° C to room temperature. The reaction is complete within a period of 20 from about 30 minutes to about 20 hours.

The hydrolysis reaction of the compound of the general formula (7) varies according to the type of R5 in the formula (7). If e.g. B. R5 is a lower alkanoyl group, the hydrolysis reaction can be carried out under the conditions of an ordinary hydrolysis reaction of an ester. In particular, the hydrolysis can advantageously be carried out in the presence of a basic compound, e.g. of sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium hydrogen carbonate; a mineral acid such as sulfuric acid or hydrochloric acid; an organic acid, such as acetic acid, an aromatic sulfonic acid, and in the presence of a customary inert solvent, such as water, methanol, ethanol, acetone, dioxane, tetrahydrofuran or benzene. The reaction temperature is usually from room temperature to about 150 ° C, preferably from 50 to 100 ° C. The reaction is completed within 1 to about 12 hours. Alternatively, when R4 is a lower alkyl group, the hydrolysis reaction can be carried out under usual hydrolysis conditions of the ether. In particular, the reaction can be carried out using aluminum 40 chloride, boron trifluoride, boron tribromide, hydrobromic acid or trimethylsilyl chloride as a catalyst and in a suitable solvent such as water, methanol, ethanol, benzene, methylene chloride, chloroform or the like at a temperature in the range of 0 to about 200 ° C, preferably at room temperature 45 to 120 ° C, for several hours to about 12 hours. In both hydrolysis reactions, the amount of the catalyst used is not subject to any specific restrictions. Usually this is used in excess of the starting compound to be hydrolyzed.

In the reaction according to formula scheme 3, the desired compound of general formula (2) can be obtained by reacting 55 a compound of general formula (8) with a compound of general formula (9). The reaction can be carried out using a basic compound, e.g. B. a dehydrohalogenating agent, in a suitable solvent at room temperature to about 200 ° C, preferably at 50 to 150 ° C, for several hours to about 15 hours. There are no particular restrictions on solvent 60, and any solvents that do not affect the reaction can be used. Examples of these are the abovementioned lower alcohols, ethers, aromatic hydrocarbons, dimethylformamide, dimethyl sulfoxide or the like and 65 ketones such as acetone, methyl ethyl ketone or the like. There are likewise no particular restrictions with regard to the dehydrohalogenating agent. Common basic compounds can be used, e.g. B. the above basic

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12

Compounds and further sodium methoxide, sodium ethoxide, potassium ethoxide, metallic potassium or the like. In the above reaction, an alkali metal iodide such as sodium iodide, potassium iodide or the like can be used as a reaction accelerator. The ratio of the amount of the compound of the formula (8) to the amount of the compound of the formula (9) is not particularly limited, but it is preferable that the latter in an equimolar amount or in a higher amount, usually in the 1- to 1 , 5 times, preferably 1 to 1.2 times, molar amount of the former compound is used. A compound of the general formula (2) can be obtained in this way, which is used as a starting material for the invention.

In the reaction according to formula schemes 2 and 3, compounds of the general formulas (4), (6) and (8) which are the starting materials for the reactions include those with substituent groups in which R1 has a meaning other than hydrogen, new compounds . These compounds can be easily prepared by using a known hydroxycarbostyril in which R1 is a hydrogen atom as a starting material and combining it with a halide in the presence of a basic compound such as an alkali metal, e.g. B. of sodium metal or potassium metal, an alkali metal amide, such as sodium amide or potassium amide, or sodium hydride, in a suitable solvent, such as benzene, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoryl triamide, at a temperature of 0 to about 70 ° C, preferably at 0 ° C to room temperature, for about 30 minutes to 12 hours, then the compound thus formed under conditions similar to the hydrolysis of a lower alkyl group of the compound of the general formula (7) according to the reaction scheme 2, hydrolyzed. In the above reaction, the ratio of the amounts of the basic compound and the halogenide to the amount of the starting compound can be suitably selected from a wide range. However, 2 to 10 times the molar amount, preferably 2 to 4 times the molar amount, of the starting material is preferably used.

Reaction scheme 5

X2-Y-X1 + H-N

(9)

(3)

(10)

In it, X1, X2, Y, R3 and R4 have the meanings given above.

10 The reaction can be carried out under conditions similar to the reaction of the compound of formula (2) with a compound of formula (3) in Reaction Scheme 1 above.

Furthermore, among the compounds of the general formula (1), a compound having a group of the formula -ch2-CH-ch2- for Y can be used in the following manner after a reaction

OH

be prepared according to formula scheme 6.

20th

25th

30th

35

Reaction scheme 6

Oli y "" k / ° \ 3

i ch2chch2v3 -

(X) ..

In c (11) R "

(8th)

(12)

U.N.

(3)

40

Reaction scheme 4

(la)

R1, R2, R3, R4, X, n and the carbon-carbon bond between the 3 and 4 positions in the carbo-45 styril skeleton have the meanings given above; X3 stands for a halogen atom and Z for a group of the formula

50 -CH - CH2

or

OH

-CH-CH2X3

(l)

therein R1, R2, R3, R4, X, X2, Y, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the meanings given above.

The desired compound according to the invention can be prepared by reacting a hydroxycarbostyril derivative of the general formula (8) with a compound of the general formula (10). The reaction conditions for the reaction according to formula scheme 4 are similar to those for the dehydrohalogenation for the reaction according to formula scheme 4.

The compound of general formula (10) used in the above reaction according to formula 4 include some new compounds. These compounds can easily be prepared by a reaction according to Formula Scheme 5.

In the reaction according to reaction scheme 6, the reaction of the compound of formula (8) with an epihalohydrin of formula (11) is carried out in the presence of a suitable basic compound, e.g. an inorganic basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, sodium hydride, sodium metal, potassium metal, sodium amide or the like; an organic basic compound, e.g. Piperidine, pyridine, triethylamine or the like; in the absence or in the presence of a suitable inert solvent, as mentioned above, e.g. B. a lower alcohol, a ketone, an ether, an aromatic hydrocarbon, water or the like. In this reaction, the ratio of the amount of the compound of the formula (11) to the amount of the compound of the formula (8) is usually an equimolar or an excess amount, preferably an equimolar to 5 to 10 times the molar amount of the latter. The reaction can take place at a temperature of 0 to

13

645 892

150 ° C, preferably 50 to 100 ° C, are carried out. In the above reaction, an epihalohydrin of the general formula (8) is reacted with the hydroxyl group in the compound of the general formula (11), whereby a (2,3-epoxy) propoxy group or a 3-halogeno-2-hydroxypropoxy- Group of the latter connection is awarded. In general, the reaction product is obtained in the form of a mixture.

The reaction product thus obtained can be as it is, e.g. B. in the form of the mixture without purification to separate the respective constituents of the mixture can be used to carry out the reaction with the piperidine derivative of the formula (3). Alternatively, the reaction product by conventional cleaning methods, e.g. B. fractional recrystallization, column chromatography or the like. Separated to separate the compound having the 2,3-epoxypropoxy group and the compound having the 3-halogeno-2-hydroxypropoxy group. The individual, separated compounds can then be reacted with a piperidine derivative of the general formula (3).

The reaction of the compound of formula (12) with a compound of formula (3) is carried out in the presence or in the absence of a suitable inert solvent at a temperature from room temperature to about 200 ° C, preferably at a temperature of 60 to 120 ° C , the reaction usually being completed within several hours to 24 hours.

In this reaction, the solvent is not particularly limited, and any solvents which do not interfere with the reaction can be used. Examples of these are the above-mentioned ethers, aromatic hydrocarbons, lower alcohols, dimethylform amide, dimethyl sulfoxide or the like.

Furthermore, if necessary in the reaction, a usual basic compound can be added to the reaction system. As the basic compound, inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride or the like; inorganic tertiary amines such as triethylamine, tripropylamine, pyridine, quinoline or the like can be used.

The ratio of the amount of the compound of formula (3) to the amount of the compound of formula (12) is usually an equimolar to excess amount, preferably an equimolar to 5 times molar amount, most preferably an equimolar to 1.2 times molar amount, that the latter.

Among the carbostyril derivatives of the general formula (1) according to the invention, a compound in which R1 has a meaning other than a hydrogen atom can be prepared from a compound in which R1 is a hydrogen atom as a starting material by a process according to reaction scheme 7.

Reaction scheme 7

styril skeletons the meanings given above; X4 represents a halogen atom and R1 'represents a lower alkenyl group, a lower alkynyl group or a lower alkyl group, which may have one or more phenyl groups as a substituted group (s).

The reaction conditions in the reaction process according to Formula Scheme 7 are similar to the reaction of the compound of the formulas (4), (6) or (8), wherein R1 is a hydrogen atom, with a halide compound, except that io is a compound of the general formula (13) is used in an equimolar to about 3 times the molar amount, preferably an equimolar amount, of a compound of the general formula (1 b).

Furthermore, among the carbostyrilde derivatives of the general formula (1) according to the invention, a compound in which the carbon-carbon bond between the 3 and 4 positions in the carbostyril skeleton is a double bond can be obtained by in which the corresponding carbon-carbon bond between the 3 and 4 positions in the 20 carbostyril skeleton is a single bond, dehydrates. Alternatively, a carbostyril derivative of the general formula (1) in which the carbon-carbon bond between the 3 and 4 positions in the carbostyril skeleton is a single bond can be obtained by catalytically reducing a compound which is the corresponding carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton a double bond. However, in the latter case, a compound having one or more halogen atoms, one or more lower alkyl groups or one or more lower alkynyl groups as a substituted group (s) is not suitable for carrying out such a catalytic reduction.

In addition to the above manner, the carbostyril derivatives of the general formula (1d) according to the invention can also be prepared by a process according to the following reaction scheme 8. 35 are manufactured.

Reaction scheme 8

_,O

\ 7

CH- - CHCH-X3 + Ilf

40

45

50

In it, R *, R2, R3, R4, X3, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the conditions given above; Z 'stands for a group of the formula

-'- oc.

55

A

-CH - CH2

or

OH

-CH-CH2X3

(HO

In it, R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-positions of the carbo-

60 In the reaction according to formula scheme 8, the reaction of the compound of formula (8) with the compound of formula (14) can be carried out under conditions which are similar to the reaction of the compound of formula (12) with a compound of formula ( 3) in reaction scheme 6. Furthermore, the reaction of the compound of formula (3) with a compound of formula (11) can also be carried out under conditions which are similar to the reaction of the compound of formula (8) with the compound of Formula (11).

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14

The carbostyril derivatives of the present invention thus prepared can be easily converted into their acid addition salts by reaction with pharmaceutically acceptable acids. The present invention also includes such acid addition salts. Examples of suitable acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like. organic acids such as acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methanesulfonic acid, benzoic acid and the like.

Among the carbostyril derivatives according to the invention, compounds in which the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton is a double bond easily form their salts by reacting with basic compounds, such as metal oxides, e.g. As potassium hydroxide, sodium hydroxide, calcium hydroxide or the like.

The carbostyril derivatives according to the invention can form quaternary salts by reacting the nitrogen atom in the piperidine ring with halogenated lower alkyl, as shown in reaction scheme 9.

Reaction scheme 9

(le)

R1, R2, R3, R4, Y, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the meanings given above; R6 stands for a lower alkyl group and Q for a halogen atom.

The reaction can advantageously be carried out in an inert solvent. As the solvent, lower alcohols such as methanol, ethanol, propanol or the like, aromatic hydrocarbons such as benzene, toluene, xylene or the like, ethers such as tetrahydrofuran, dioxane or the like, chloroform, trichlorethylene, dimethylformamide (DMF), dimethyl sulfoxide (DMSO ), Hexametaphosphoryl triamide or the like.

The ratio of the amount of the compound of the formula (15) to the amount of the compound of the formula (1) is usually at least an equimolar amount, preferably an equimolar to 5 times the molar amount of the latter compound. The reaction is usually carried out at a temperature of 0 to about 200 ° C, preferably from room temperature to 80 ° C, and for a period of 1 to 8 hours.

Among the compounds of the general formula (Ie) according to the invention which have been prepared by the process according to Reaction Scheme 9, when Q denotes a halogen atom with an atomic number which is greater than that of the chlorine atom, the compound mentioned can be converted into another compound the Q is a chlorine atom can be converted by reacting the compound with silver chloride. Similarly, when Q represents a halogen atom with a number larger than that of the bromine atom, the compound can be converted into another compound in which Q is a bromine atom by reacting the compound with silver bromide. Such a halogen atom conversion reaction can advantageously be carried out in the presence of a solvent, e.g. an above-mentioned lower alcohol,

of dimethylformamide, dimethyl sulfoxide or water. The ratio of the amount of silver halide to the amount of starting material is at least an equimolar amount, preferably an equimolar to 6 times the molar amount, 5 of the latter. The reaction can be carried out at a temperature from 0 to about 80 ° C, preferably at room temperature to 50 ° C, within a period of 5 to about 24 hours.

The desired compounds, such as those prepared by process 10 in accordance with the above reaction schemes, can easily be isolated and purified by customary separation measures, such as solvent extraction, dilution, recrystallization, column chromatography, preparative thin-layer chromatography, etc.

The compounds according to the invention should also include their optical isomers.

For antihistamine agents, the compounds of the general formula (1) can be used in the form of a pharmaceutical preparation together with the customary, pharmaceutically acceptable carriers. Examples of carriers which are used according to the desired form of the pharmaceutical preparation are diluents or excipients, e.g. Fillers, diluents, binders, humectants, disintegrants, surfactants and lubricants.

There are no particular restrictions on the form of administration, and the compounds of the present invention can be used in any desired unit form as antihistamines. Typical unit forms are e.g. Tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection liquids (solutions and suspensions) and ointments. For deformation in the form of tablets, carriers which are usually widely used in this field can also be used, e.g. B. excipients such as lactose, sucrose, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silica; Binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, calcium phosphate and polyvinyl pyrrolidone; Disintegrating agents, such as dried starch, sodium alginate, agar-agar powder, laminalia powder, sodium hydrogen carbonate, calcium carbonate, tween wetting agents, sodium lauryl sulfate, monoglyce-45 ride of stearic acid, starch, lactose; Disintegration inhibitors such as sucrose, stearin, coconut butter, hydrogenated oil; Absorption accelerators, such as quaternary ammonium bases; Sodium lauryl sulfate; Wetting agents such as glycerin or starch; Adsorbents, such as starch, lactose, kaolin, bensonitite, colloidal silica; Lubricants such as purified talc, stearic acid salt, boric acid powder, macrogol, solid poly-ethylene glycol etc. In the case of tablets, a coating with the usual coating materials can also be carried out to make tablets coated with sugar, tablets coated with gelatin-55, tablets containing Films are coated, or to produce double-layer tablets and multi-layer tablets.

Carriers which are known and are widespread in this field can be used to deform into pills, e.g. B. 60 excipients such as glucose, lactose, starch, coconut butter, hydrogenated vegetable oils, kaolin and talc; Binders such as powdered gum arabic, powdered tragacanth, gelatin and ethanol; Disintegrators such as Laminaria and agar.

Carriers which are known and widely used in this field can be used to deform them into suppositories, e.g. Polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides.

15

645 892

Solutions and suspensions are sterilized to produce injectable preparations. They are preferably isotonic with blood. In the preparation of injectable preparations, all carriers which are usually used for this can be used, such as. B. water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, poly-oxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters. In these cases, adequate amounts of sodium chloride, glucose or glycerin can be added to the desired preparations to make them isotonic. Furthermore, the usual dissolving agents, buffering agents, analgesics, preservatives can be added, as well as coloring materials, preservatives, aromatizing agents, seasonings, sweeteners and other drugs.

For the preparation of pastes and creams, customary diluents can be used, e.g. B. white petroleum jelly, paraffin, glycerin, cellulose derivatives, polyethylene glycols, silicones and bentonite.

The amount of compounds of the general formula (1) or their acid addition salts in the antihistaminic agents is not particularly limited. It can be appropriately selected within a wide range.

However, 1 to 70% by weight, based on the total composition, is usually preferred.

The above-mentioned antihistamines and CNS depressants can be used in various forms, depending on the application, without any restrictions. So z. B. orally administered tablets, pills, solutions, suspensions, emulsions, granules and capsules. Injectable preparations are either administered intravenously individually or mixed with infusion solutions such as glucose solutions and amino acid solutions. If necessary, the injectable preparations can be administered individually intramuscularly, intracutaneously, subcutaneously or intraperitoneally.

The dose of the antihistamines according to the invention is suitably selected depending on the use, the purpose and the condition of the symptoms. Usually, a medicine containing 40 to 2 mg / kg / day of the compound represented by the general formula (1) or its acid addition salt can be administered 3 to 4 times a day.

Example for the preparation of tablets -1 Tablets with the following composition were produced according to the usual working methods. l-methyl-7- [3- (4-benzyl-l-piperidyl) -

propoxy] -3,4-dihydrocarbostyril monooxalate 5 mg

Corn starch 132 mg

Magnesium stearate 18 mg

Lactose 45 mg total 200 mg

Example for the preparation of tablets - 2 Tablets with the following composition were produced according to the usual working methods. l-methyl-5- [3- (4-benzyl-l-piperidyl) -

propoxy] -3,4-dihydrocarbostyril monooxalate 5 mg

Corn starch 132 mg

Magnesium stearate 18 mg

Lactose 45 mg total 200 mg

Example of the preparation of tablets - 3 Tablets with the following composition were produced according to the customary procedures. 7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) -

propoxy] -3,4-dihydrocarbostyril 5 mg

Corn starch 132 mg

Total magnesium stearate lactose

18 mg 45 mg 200 mg

Example of the preparation of tablets - 4 According to the usual procedures, tablets with the following composition were produced. 4-phenyl-l- [3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-7-yl-oxy) propyl] methyl

piperidinium chloride semihydrate 5 mg

Corn starch 132 mg

Magnesium stearate 18 mg

Lactose 45 mg

15 total 200 mg

Example of the preparation of tablets - 5 Tablets with the following composition were produced according to the customary procedures. 20 5- [3- (4-hydroxy-4-phenyl-l-piperidyl) -

propoxy] -3,4-dihydrocarbostyril 5 mg

Corn starch 132 mg

Magnesium stearate 18 mg

Lactose 45 mg

25 total 200 mg

30th

Pharmacological test 1 Test of antihistamine activity A method using the isolated guinea pig ileum is generally used as a method for determining the antihistamine activity of a compound in vitro. The pharmacological test of the compounds according to the invention was carried out according to this method as follows.

40 A male guinea pig weighing 300 to 500 g body weight was sacrificed by bleeding. An ileum with a length of 15 cm was peeled out of the ileocecal area and immersed in a Tyrode solution (the latter was made from 8.0 g NaCl, 0.2 g KCl, 0.2 g CaCl2, «1.0 g glucose, 1.0 g NaHC03.0.065 g NaHP04-2H20 and 0.2135 g MgCl2-6H20 with the addition of water to a total volume of 100 ml). The ileum tissue was then cut to a length of 2.5 to 3.0 cm and hung in an organ bath filled with 30 ml of Tyrode solution 50. The organ bath was kept at a temperature of 36 ° C and a mixed gas consisting of 5% CO 2 and 95% 02 was blown into the bath. 10 min after the blowing, IO "6 M histamine was added to the bath to examine the sensitivity of the tissue. A response curve 55 (control) regarding the dose of histamine was obtained. After the dose of the histamine reaction curve (control) became constant 10g / ml of the test compound was added to the bath and histamine was further added 5 minutes later to obtain a dose-response curve. The ileum retraction was carried out with a recorder by an isotonic transducer (TD-112S , produced by Nihon Koden) The antihistamine activity of the test compound was determined as pA2 value according to the “Van Rossam” method [JM Van Rossam, Arch. Inst. 65 Pharmacodyn., 143, 299 (1963)], the maximum retraction of the ileum caused by histamine according to the control curve was estimated to be 100%, and the results obtained are shown in Table 1.

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16

Test compounds [Compounds according to the invention (No. 1 to No. 15)]

connection

No. Name of the connection

1 5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril

2 l-Methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate

3 l-propargyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride

4 l-Methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride

5 4-Methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril

6 l-Allyl-5- [2-hydroxy- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate

7 l-Ethyl 5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate

8 8-Bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril

9 7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril

10 l-Methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate

11 4-Phenyl-l- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetrahydro-quinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide

12 l-Benzyl-5- [2-hydroxy- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate

13 4-phenyl-7- [3- (4-phenyl-l-piperidyl) propoxy] carbostyril monohydrochloride

14 5-3- [4- (4-Hydroxy-4-phenyl) -1-piperidyl] -3,4-dihydrocarbostyril

15 7-3- [4- (4-Acetyl-4-phenyl) -1-piperidyl] -3,4-dihydrocarbostyril

[Reference compounds A and B] A Diphenylhydramine hydrochloride B Chlorpheniramine maleate

Table 1

Pharmacological test 2 Acute toxicity test The individual compounds according to the invention were administered orally to male rats in order to determine the acute toxicity. The results obtained are shown in Table 2.

Table 2

10th

15

20th

25th

Test connections

Acute toxicity (LD50 mg / kg)

1

> 1000

2nd

> 1000

3rd

> 1000

4th

> 1000

5

> 1000

6

> 1000

7

> 1000

8th

> 1000

9

> 1000

10th

> 1000

11

> 1000

12

> 1000

13

> 1000

14

> 1000

15

> 1000

Connection no.

pA2 value

(compounds according to the invention)

1

9.52

2nd

10.70

3rd

9.73

4th

11.00

5

9.59

6

9.54

7

9.65

8th

8.39

9

9.89

10th

9.62

11

8.23

12

10.70

13

9.73

14

9.30

15

9.92

(Reference connections)

A

8.15

B

9.00

The invention is illustrated in the examples. The preparation of the compounds which are used as starting materials is described in the reference examples. The preparation of the compounds according to the invention is explained in the examples.

Reference Example 1 35 20.5 g of 5-acetyloxy-3,4-dihydrocarbostyril was dissolved in 200 ml of acetic acid. 16 g of bromine, dissolved in 60 ml of acetic acid, were added dropwise to this solution with water cooling and stirring over the course of 30 minutes. The reaction was continued for 2 hours at the same temperature. Then the 300 ml of water was added to this reaction mixture and the mixture was allowed to stand for 3 hours. Crystals formed in the mixture were filtered off and recrystallized from methanol. 21 g of 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril were obtained in the form of colorless, needle-shaped crystals, mp. 237 to 239 ° C. 45 Then, 21 g of the 8-bromo-5-acetyloxy-3,4-dihydrocarbostyril thus obtained was dispersed in 150 ml of 8N hydrochloric acid, and the mixture was refluxed for 3 hours. After the reaction mixture had cooled, insoluble substances were filtered off, washed with water, dried and recrystallized from methanol-water. 14 g of 5-bromo-5-hydroxy-3,4-dihydrocarbostyril were obtained in the form of colorless, acicular crystals, mp. 212 to 213 ° C.

Reference Example 2 35.4 g of 7-methoxy-3,4-dihydrocarbostyril was dissolved in 300 ml of 55 acetic acid. While cooling with ice and stirring, 27 g of sulfuryl chloride, dissolved in 100 ml of acetic acid, were added dropwise. Then the reaction mixture was allowed to stand overnight. The reaction mixture was poured into 11 ice-water and the precipitate was collected by filtration, washed with water, dried and recrystallized from methanol. 30 g of 6-chloro-7-methoxy-3,4-dihydrocarbostyril, mp. 212 ° C, were obtained in the form of colorless, needle-shaped crystals.

30 g of the 6-chloro-7-methoxy-3,4-dihydrocarbostyril thus obtained were dispersed in 300 ml of a 47% aqueous hydrobromic acid solution and the mixture was refluxed for 4 hours. After the reaction mixture had cooled, the insoluble substances were collected by filtration, washed with water, dried and from methanol-chloroform

60

65

17th

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recrystallized. 25 g of 6-chloro-7-hydroxy-3,4-dihydrocarbostyril, mp. 264 to 266 ° C, were obtained in the form of colorless, needle-shaped crystals.

Reference Example 3 16.4 g of 5-hydroxy-3,4-dihydrocarbostyril was dissolved in 300 ml of acetic acid. While stirring, 80 ml of acetic acid containing 14 g of chlorine was added dropwise at room temperature, and the reaction was continued for 3 hours with stirring. The reaction mixture was poured into 500 ml of water and left to stand for 1 hour. The precipitate thus formed was collected by filtration, washed with water, dried and recrystallized from methanol. 16 g of 6,8-dichloro-5-hydroxy-3,4-dihydrocarbostyril were obtained in the form of colorless, needle-shaped crystals, mp. 259 to 260 ° C.

Reference Example 4 20.0 g of 8-bromo-5-hydroxy-3,4-dihydrocarbostyril and 18 g of potassium carbonate were dispersed in 160 ml of isopropanol. Then 40 ml of epichlorohydrin were added and the mixture was reacted at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue obtained was mixed with 100 ml of 2N sodium hydroxide solution and carried out well. The insoluble matter formed was recovered by filtration, washed with water and dried, whereby crude crystals were obtained. The recrystallization of the crude crystals from methanol gave 18.5 g of 8-bromo-5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril in the form of colorless, needle-shaped crystals, mp. 220 to 222 ° C.

Reference Example 5 16.4 g of 5-hydroxy-3,4-dihydrocarbostyril and 3.7 g of sodium hydroxide were placed in 100 ml of methanol and the mixture was stirred at 40 to 50 ° C for 3 hours. 150 ml of epichlorohydrin were then added and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue thus obtained was recrystallized from methanol-water (1: 1), whereby 18.5 g of 5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril, mp. 172 to 173 ° C, were obtained in the form of colorless, amorphous crystals.

Reference Example 6 16.3 g of 5-hydroxy-3,4-dihydrocarbostyril and 9 g of potassium hydroxide were mixed with 150 ml of isopropanol and stirred at 70 to 80 ° C. for 30 minutes. 25 g of 1,3-bromochloropropane were then added and the mixture was heated under reflux for 6 hours. After the completion of the reaction, the reaction mixture was poured into 200 ml of an aqueous 2N sodium hydroxide solution, and the insoluble matter formed was collected by filtration, washed with water and dried. The crude crystals thus obtained were recrystallized from ethanol, giving 18.5 g of 5- (3-chloropropoxy) -3,4-dihydrocarbostyril in the form of colorless, needle-shaped crystals, mp 176 to 178 ° C.

Reference Example 7 24 g of 4-phenylpiperidine, 14 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and the mixture was stirred at 50 to 60 ° C. for 1 hour. The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous solution and the organic layer was extracted with chloroform. The chloroform layer was then washed with water, dried and the chloroform was distilled off. The residue thus obtained was purified by silica gel column chromatography (whereby only the main product was obtained from the uppermost part of the acid). 15.3 g of l-chloro-3- (4-phenylpiperidinyl) propane were obtained in the form of a colorless, oily substance. Then this oily substance was distilled under reduced pressure, thereby

11g of a fraction of a distillate with a boiling point of 112 to 115 ° C / 0.1 mmHg were obtained. A portion of this distillate was converted to the hydrochloride and recrystallized from ethanol to give 1-chloro-3- (4-phenyl-1-piperidyl) propane-mono-5 hydrochloride, mp. 167-169 ° C, in the form of a colorless, acicular form Crystals were obtained.

Reference Example 8 io Using a method similar to Reference Example 7, l-chloro-2-methyl-3- (4-phenyl-l-piperidyl) propane was obtained in the form of a colorless, oily substance, bp. 114 to 116 ° C./0 , 1 mmHg.

15

Reference Example 9 16.0 g of 4-hydroxy-4-phenylpiperidine, 24 g of 1-chloro-3-bromopropane and 15 g of triethylamine were mixed with 100 ml of dimethylformamide and the mixture was stirred at 50 to 60 ° C. for 1 hour . The reaction mixture was poured into 200 ml of saturated sodium chloride aqueous solution. The organic layer was extracted with chloroform. The chloroform layer was then washed with water, dried and the chloroform was distilled off. The residue thus obtained was purified by silica gel column chromatography (with only the main product being obtained as the uppermost part in the column). 14.3 g of l-chloro-3- (4-hydroxy-4-phenyl-l-piperidyl) propane were obtained in the form of a colorless, oily substance. Then this oily substance was distilled under reduced pressure, whereby a fraction of the distillate was obtained. The fraction of the distillate was converted to the form of the hydrochloride and the product was recrystallized from ethanol. 1-Chloro-3- (4-hydroxy-4-phenyl-l-piperidyl) propane monohydrochloride, mp. 192 to 195 ° C., was obtained in the form of colorless, needle-shaped crystals.

example 1

4.8 g of 5- (3-chloropropoxy) -3,4-dihydrocarbostyril and 4.2 g of 4-benzylpiperidine were mixed with 40 ml of toluene and the mixture was heated to reflux for 24 hours. After the reaction mixture had cooled, the precipitate formed was collected by filtration, washed with water and then recrystallized from ethanol. 6.3 g (yield 76%) of 5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyrilin 45 were obtained in the form of colorless, needle-like crystals, mp. 143 to 145 ° C.

Example 2

4.9 g of l-methyl-7- (3-chloropropoxy) -3,4-dihydrocarbostyril, 4.2 g of 4-benzylpiperidine and 3 g of triethylamine were mixed with 60 ml of dimethylformamide. The mixture was heated to 70-80 ° C for 8 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue thus obtained was mixed with aqueous 5% 55 sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried. The chloroform was then distilled off. The residue obtained was dissolved in 30 ml of acetone, and a 5% aqueous solution of oxalic acid in 60 acetone was added with stirring to adjust the pH to 4.5. Then it was left standing. The precipitate formed was collected by filtration, washed with acetone and then recrystallized from ethanol-ether. 7.9 g (yield 86%) of l-methyl-7- [3- (4-benzyl-1-piperidyl) propoxy] -65 3,4-dihydrocarbostyril monooxalate were obtained in the form of a colorless powder, mp. 175 up to 177 ° C.

Following a procedure similar to that in Example 2, the compounds of Examples 3 to 16 were prepared as follows.

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18th

Example 3

l-propargyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride monohydrate; colorless, needle-shaped crystals (from methanol ether); Mp 172 ° C (dec.).

Example 4

l-methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; colorless, needle-shaped crystals (from ethanol ether); Mp 130-133 ° C.

Example 5

l-hexyl-7- [3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, needle-shaped crystals (from isopropanol); Mp 168 to 170 ° C.

Example 6

1- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, needle-shaped crystals (from methanol-water); Mp 210-213 ° C.

15

Example 7

6,8-dichloro-5- [2-methyl-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 125-126 ° C.

Example 8

5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 213-215 ° C.

Example 9

5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin-benzene); Mp 143 to 145 ° C.

Example 10

7- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, prism-like crystals (from ethanol); Mp 175 to 177 ° C.

Example 11

7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; yellowish, needle-shaped crystals (from ethanol); Mp 252-254 ° C.

Example 12

4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril monohydrochloride dihydrate; colorless, acicular crystals (from ethanol); Mp 241 to 242 ° C.

Example 13

5- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril hydrochloride; colorless, needle-shaped crystals (from methanol); Mp 200 ° C.

Example 14

4-methyl-6- {3- [4- (4-methylphenyl) -1-piperidyl] propoxy} • carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 256-259 ° C (dec.).

Example 15

4-methyl-6-j 3- [4- (4-chlorophenyl) -l-piperidyl] propoxy carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 263-265 ° C.

Example 16

l-isopentyl-6- {2-hydroxy-3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril monooxalate; colorless, flake-like crystals (from ethanol); Mp 199-201 ° C.

Example 17

2.7 g of 7- (5-bromopentoxy) -3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperidine and 1.5 g of triethylamine were mixed with 30 ml of dimethylformamide and the mixture was heated at 60 to 70 ° C for 6 hours . The reaction mixture was then concentrated to dryness under reduced pressure, the residue obtained was added to an aqueous 5% sodium hydrogen carbonate solution and stirred. The insolubles that formed were collected by filtration, washed with water and dried. Recrystallization from ligroin gave 3.6 g (yield 88%) of 7- [5- (4-benzyl-l-piperidyl) pentoxy] -3,4-dihydrocarbostyril in the form of colorless, platelet-like crystals, mp. 100 to 102 ° C. .

20 Example 18

2.5 g of 4-methyl-6- (3-chloropropoxy) carbostyril, 1.8 g of sodium iodide were mixed with 50 ml of acetone and the mixture was stirred at 50 ° C. for 1 hour and 50 ml of dimethylformamide 25 were added. Acetone was removed by distillation under reduced pressure. 1.5 g of triethylamine and 1.6 g of 4-benzylpiperidine were added to the residue obtained, and the mixture was heated at 70 to 80 ° C. for 7 hours with stirring. The reaction mixture was then concentrated to dryness under reduced pressure, and to the residue obtained was added 60 ml of an aqueous 5% sodium hydrogen carbonate solution, and the mixture was stirred to obtain insoluble matters. The insolubles were collected by filtration, washed with water and then recrystallized from methanol. 3.2 g (yield 82%) of 4-methyl-6- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril were obtained in the form of yellowish, primer-like crystals, mp. 177 to 178 ° C.

A method similar to that described in Example 18 gave the compounds of Examples 19 to 24 as follows 40.

Example 19

4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril; colorless, needle-shaped crystals (from methanol); Mp 183 to 184 ° C.

45 Example 20

4-phenyl-7- [3- (4-phenyl-l-piperidyl) propoxy] carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol ether); Mp 238 to 241 ° C.

50

55

60

65

Example 21

4-methyl-6- [3- (4-benzyl-1-piperidyl) propoxy] carbostyril; yellow-brown, prism-like crystals (from methanol); Mp 177 to 178 ° C.

Example 22

4-methyl-6- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril monohydrochloride; colorless, powdery crystals (from ethanol-acetone ether); Mp 217 ° C.

Example 23

4-methyl-6 - {3- [4- (4-methylphenyl) -1-piperidyl] propoxy} carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 256 to 259 ° C (dec.).

Example 24

4-methyl-6- {3- [4- (4-chlorophenyl) -1-piperidyl] propoxy} • carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 263-265 ° C.

19th

645 892

Example 25

2.6 g of l-allyl-5- (2-hydroxy-3-chloropropoxy) -3,4-dihydrocarbostyril, 1.5 g of triethylamine and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of dimethylformamide and the mixture was stirred for 5 hours at 80 to 90 ° C. The reaction mixture was poured into 80 ml of an aqueous 5% sodium hydrogen carbonate solution, the organic layer was extracted with chloroform, and the chloroform layer was washed with water and dried. The chloroform was then removed by distillation and the residue obtained was dissolved in 30 ml of acetone. A 5% solution of oxalic acid in acetone was also added to adjust the pH to 4.5. The crystals formed were collected by filtration and washed with acetone. Recrystallization from ethanol gave 4.3 g (yield 82%) of l-allyl-5- [2-hydroxy- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril-mono-oxalate in the form of colorless acicular Crystals, mp. 178 to 180 ° C.

By a method similar to that described in Example 25, the compounds of Examples 26 to 36 were obtained as follows.

Example 26

l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery crystals (from ethanol ether); Mp 213-214 ° C (dec.).

Example 27

l-ethyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, acicular crystals (from ethanol); Mp 164-169 ° C.

Example 28

6-bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 165-166 ° C.

Example 29

5- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol);

Mp. 207 to 208 ° C.

Example 30

6- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, platelet-like crystals (from ethanol); Mp 170-171 ° C.

Example 31

7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from isopropanol); Mp 149 to 150 ° C.

Example 32

l-allyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 92 ° C.

Example 33

l-allyl 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyrii monooxalate; yellowish, needle-shaped crystals (from methanol); Mp 208 ° C (dec.).

Example 34

l-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery crystals (from ethanol ether); Mp 150-152 ° C.

Example 35

l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 141-143 ° C.

Example 36

l-isopentyl-6-j2-hydroxy-3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl] propoxy [-3,4-dihydrocarbostyril monooxalate; colorless, flake-like crystals (from ethanol); Mp 199-201 ° C.

5

Example 37

2.4 g of l-methyl-5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of methanol.

10 mixes. The mixture was refluxed for 3 hours and the reaction mixture was concentrated under reduced pressure. The residue thus obtained was dissolved in 30 ml of acetone and a 5% solution of oxalic acid and acetone was at room temperature to adjust the pH

15 4.5 added; then the mixture was allowed to stand. The precipitates formed were collected by filtration, washed with acetone and recrystallized from ethanol-ether; 3.9 g (yield 78%) of l-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril-mono-

20 oxalate in the form of a colorless powder, mp. 150 to 152 ° C.

By a method similar to that described in Example 37, the compounds of Examples 38 to 47 were obtained as follows.

25 Example 38

6- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, platelet-like crystals (from ethanol); Mp 170-171 ° C.

Example 39

30 l-ethyl 5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, acicular crystals (from ethanol); Mp 164-169 ° C.

Example 40

35 8-bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 165-166 ° C.

40 Example 41

7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from isopropanol); Mp 149 to 150 ° C.

Example 42

45 5- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp. 207 to 208 ° C.

Example 43

so l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 141-143 ° C.

Example 44

55 l-isopentyl-6-j 2-hydroxy-3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl] propoxy | -3,4-dihydrocarbostyril monooxalate; colorless, flake-like crystals (from ethanol); Mp 199-201 ° C.

60 Example 45

l-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery crystals (from ethanol ether); Mp 150-152 ° C.

65 Example 46

l-allyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 92 ° C.

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20th

Example 47

l-allyl 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; yellowish, needle-shaped crystals (from methanol); Mp 208 ° C (dec.).

Example 48

3.8 g5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and 0.6 g sodium hydride (50% in oil) were mixed with stirring in 60 ml dimethylformamide for 1 hour. Then 1.4 g of propargyl bromide was added to the mixture and stirred at room temperature for 2 hours. The reaction mixture was poured into 100 ml of saturated sodium chloride aqueous solution and the organic layer was extracted with chloroform. The chloroform layer was dried and the chloroform was distilled off. The residue obtained was recrystallized from ethanol-hydrochloric acid; 4.1 g (yield 87%) of l-propoargyl-5- [3- (4-benzyl-l-piperidyl) propoxyl-3,4-dihydrocarbostyril mono-hydrochloride monohydrate were obtained in the form of colorless, needle-shaped crystals, Mp 172 ° C (dec.).

By a method similar to that described in Example 48, the compounds of Examples 49 to 54 were obtained as follows.

Example 49

l-methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; colorless, needle-shaped crystals (from ethanol ether); Mp 130-133 ° C.

Example 50

l-n-hexyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, needle-shaped crystals (from isopropanol); Mp 168 to 170 ° C.

Example 51

1- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, needle-shaped crystals (from methanol-water); Mp 210-213 ° C.

Example 52

l-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery substance (from ethanol ether); Mp 175-177 ° C.

Example 53

l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 141 to 143 ° C.

Example 54

l-isopentyl-6-j2-hydroxy-3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl] propoxy | -3,4-dihydrocarbostyril monooxalate; colorless, flake-like crystals (from ethanol); Mp 199-201 ° C.

Example 55

2.4 g of 7-hydroxy-4-phenylcarbostyril and 0.8 g of potassium hydroxide were mixed with 60 ml of methanol and the mixture was concentrated to dryness under reduced pressure. To the residue obtained was added 60 ml of dimethylformamide and mixed thoroughly. The mixture was then mixed with 5 g of l- (3-chloropropyl) -4-phenylpiperidine and heated to 70 to 80 ° C. for 8 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure, 60 ml of aqueous 5% sodium hydrogen carbonate solution were added to the residue obtained and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried and the chloroform was removed by distillation. 30 ml of methanol and 5 ml of concentrated hydrochloric acid were added to the residue obtained, and the mixture was concentrated under reduced pressure. The residue was crystallized with ethanol and recrystallized from methanol. 2.8 g (yield 58%) of 4-phenyl-7- [3- (4-phenyl-l-piperidyl) propoxy] carbostyril monohydrochloride were obtained in the form of colorless, needle-shaped crystals; Mp 238 to 241 ° C.

By a method similar to that described in Example 55, the compounds of Examples 56 to 76 were obtained as follows.

Example 56

l-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery substance (from ethanol ether); Mp 175 to 177 ° C.

Example 57

l-propargyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride monohydrate; colorless, needle-shaped crystals (from methanol ether); Mp 172 ° C (dec.).

Example 58

l-methyl-5- [3- (4-benzyl-.l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; colorless, needle-shaped crystals (from ethanol ether); Mp 130-133 ° C.

Example 59

l-hexyl-7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, needle-shaped crystals (from isopropanol); Mp 168 to 170 ° C.

Example 60

1- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyriI monooxalate; colorless, needle-shaped crystals (from methanol-water); Mp 210-213 ° C.

Example 61

l-allyl-5- [2-hydroxy- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, acicular crystals (from ethanol); Mp 178-180 ° C.

Example 62

l-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery crystals (from ethanol ether); Mp 150-152 ° C.

Example 63

l-benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 141-143 ° C.

Example 64

5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 213 to 215 ° C.

Example 65

5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, needle-shaped crystals (from ligroin-benzene); Mp 143-145 ° C (dec.).

Example 66

7- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, prism-like crystals (from ethanol); Mp 175 to 177 ° C.

5

10th

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25th

30th

35

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45

50

55

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65

21st

645 892

Example 67

l-allyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 92 ° C.

Example 68

l-allyl 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; yellowish, needle-shaped crystals (from methanol); Mp 208 ° C (dec.).

Example 69

4-methyl-6- [3- (4-benzyl-1-piperidyl) propoxy] carbostyril; yellow-brown, prism-like crystals (from methanol); Mp 177-178 ° C.

Example 70

4-methyl-6- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril monohydrochloride; colorless, powdery crystals (from ethanol-acetone ether); Mp 217 ° C.

Example 71

5- [3- (4-phenyl-l-piperidyl) propoxy] carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 200 ° C.

Example 72

7- [3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril monohydrochloride; yellowish, needle-shaped crystals (from ethanol); Mp 252-254 ° C.

Example 73

4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril monohydrochloride dihydrate; colorless, acicular crystals (from ethanol); Mp 241 to 242 ° C.

Example 74

4-methyl-6-- | 3- [4- (4-methylphenyl) -l-piperidyl] propoxy} carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 256-259 ° C (dec.).

Example 75

4-methyl-6-- | 3- [4- (4-chlorophenyl) -l-piperidyl] propoxy} • carbostyril monohydrochloride; colorless, needle-shaped crystals (from methanol); Mp 263-265 ° C.

Example 76

l-isopentyl-6- | 2-hydroxy-3- [4- (3,4,5-trimethoxyphenyl) -1-piperidyl] propoxy [-3,4-dihydrocarbostyril monooxalate; colorless, flake-like crystals (from ethanol); Mp 199-201 ° C.

Example 77

2.4 g of 6,8-dichloro-5-hydroxy-3,4-dihydrocarbostyril and 0.8 g of granular potassium hydroxide were mixed with 60 ml of methanol and the mixture was concentrated to dryness under reduced pressure. 60 ml of dimethylformamide were added to the residue obtained and mixed well. Then 5 g of l-chloro-2-methyl-3- (4-phenylpiperidyl) propane were added to the mixture and the mixture was heated at 70 to 80 ° C. for 8 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure, 60 ml of an aqueous 5% sodium hydrogen carbonate solution were added and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried. The chloroform was removed by distillation, and the residue obtained was purified by silica gel column chromatography and recrystallized from ligroin. 1.6 g (yield 35%) of 6,8-dichloro-5- [2-methyl-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril in a colorless, acicular crystals, mp 125 to 126 ° C.

By a method similar to that described in Example 77, the compounds of Examples 78 to 82 were obtained as follows.

Example 78

5- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 143 to 145 ° C.

Example 79

7- [5- (4-Benzyl-l-piperidyl) pentoxy] -3,4-dihydrocarbostyril; colorless, platelet-like crystals (from ligroin); Mp 100 to 102 ° C.

Example 80

l-methyl-6- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril; yellowish, prism-like crystals (from methanol); Mp 177 to 178 ° C.

Example 81

4-methyl-7- [3- (4-benzyl-l-piperidyl) propoxy] carbostyril; colorless, needle-shaped crystals (from methanol); Mp 183-184 ° C.

Example 82

8-bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 165-166 ° C.

Example 83

1.8 g of l-methyl-5-hydroxy-3,4-dyhydrocarbostyril and 2.3 g of 4-benzyl-l- (2,3-epoxypropyl) piperidine were mixed with 30 ml of methanol and the mixture was stirred for 3 hours. heated at reflux. The reaction mixture was concentrated under reduced pressure and the residue obtained was dissolved in 30 ml of acetone. Then a 5% solution of oxalic acid in acetone was added to adjust the pH to 4.5 and the mixture was allowed to stand. The precipitate formed was collected by filtration, washed with acetone and recrystallized from ethanol-ether. 3.5 g (yield 63%) of l-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate were obtained in the form of a colorless, pul -formed substance, mp. 150 to 152 ° C.

By a method similar to that described in Example 83, the compounds of Examples 84 to 95 were obtained as follows.

Example 84

l-benzyl-5-2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery substance (from ethanol ether); Mp 213-214 ° C.

Example 85

l-ethyl-5-2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, acicular crystals (from ethanol); Mp 164-169 ° C.

Example 86

8-bromo-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 165-166 ° C.

Example 87

5- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol);

Mp 207 to 208 ° C.

Example 88

6- [2-Hydroxy-3- (4-phenyl-1-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, platelet-like crystals (from ethanol); Mp 170-171 ° C.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

645 892

22

Example 89

7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from isopropanol); Mp 149 to 150 ° C.

Example 90

l-allyl 5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, acicular crystals (from ethanol); Mp 178-180 ° C.

Example 91

l-allyl-5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from methanol); Mp 92 ° C.

Example 92

l-allyl 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyrii monooxalate; yellowish, needle-shaped crystals (from methanol); Mp 208 ° C.

Example 93

l-methyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, powdery crystals (from ethanol ether); Mp 150-152 ° C.

Example 94

5- [2-Hydroxy-3- (3,4,5-trimethoxyphenyl) propoxy] -3,4-dihydrocarbostyril monooxalate; colorless, flake-like crystals (from ethanol); Mp 199-201 ° C.

Example 95

2.0 g of 5- [2-hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and 3 g of methyl iodide were mixed with 30 ml of dimethylformamide and the mixture was stirred at 50 for 5 hours stirred up to 60 ° C. The reaction mixture was concentrated under reduced pressure, the residue obtained was mixed with 50 ml of acetone and stirred. The precipitate formed was collected by filtration, washed with acetone and recrystallized from methanol-ethanol; 1.7 g of 4-phenyl-1- [2-hydroxy-3- (2-oxo-l, 2,3,4-tetrahydroquinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide were obtained Form of a colorless, powdery substance, mp. 242 to 243 ° C.

Using a method similar to that described in Example 95, the compounds of Examples 96 and 97 were obtained as follows.

Example 96

l-phenyl-l- [2-hydroxy-3- (l-allyl-2-oxo-l, 2,3,4-tetrahydroquinoline-5-yl-oxy) propyl] -l-methylpiperidinium iodide; colorless, needle-shaped crystals (from isopropanol-acetone); Mp 179-180 ° C.

Example 97

4-benzyl-l- [2-hydroxy-3- (l-benzyl-oxo-l, 2,3,4-tetrahydro-quinolin-5-yl-oxy) propyl] -l-methylpiperidinium iodide; yellowish, needle-shaped crystals (from ethanol ether); Mp 135 to 139 ° C.

Example 98

2.0 g of 4-phenyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium iodide semihydrate were dissolved in 150 ml of methanol and 100 ml of water dissolved. 3.0 g of silver chloride were added and the mixture was stirred in a dark and cool place for 24 hours. The reaction mixture was filtered and the mother liquor obtained was concentrated to dryness under reduced pressure. The residue was recrystallized from isopropanol-acetone ether; 1.0 g of 4-phenyl-l- [3- (2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl-oxy) propyl] -1-methylpiperidinium chloride semihydrate were obtained in the form of colorless , powdery crystals, mp. 211 to 213 ° C.

10th

Example 99

2.4 g of 7- (3-chloropropoxy) -3,4-dihydrocarbostyril and 4.0 g of 4-hydroxy-4-phenylpiperidine were mixed with 150 ml of toluene and heated under reflux for 24 hours. After the reaction mixture had cooled, the precipitates formed were collected by filtration, washed with water and then recrystallized from ethanol. 2.8 g of 7- [3- (4-hydroxy-4-phenyl-piperidyl) propoxy] -3,4-dihydrocarbostyril were obtained in the form of colorless, flake-like crystals, mp. 215 ° C.

By a method similar to that described in Example 99, the compounds of Examples 100 to 107 were obtained as follows.

15

Example 100

5- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from methanol); Mp 265 to 266 ° C.

Example 101

7-j 3- [4-Hydroxy-4- (4-chlorophenyl) -1-piperidyl] propoxy J-3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 189 to 190 ° C.

25th

Example 102

5- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; light yellowish, prism-like crystals (from ethanol); Mp 165 ° C.

Example 103

30 7- [3- (4-Acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from isopropanol); Mp 159 to 160 ° C.

Example 104

35 6- [2- (4-acetyl-4-phenyl-l-piperidyl) ethoxy] carbostyril; colorless, acicular crystals (from ethanol); Mp 158 to 160 ° C.

Example 105

7-j 3- [4-hydroxy-4- (4-methylphenyl) -1-piperidyl] propoxy j - 40 3,4-dihydrocarbostyril; colorless, flake-like crystals (from ethanol); Mp 188-189 ° C.

Example 106

45 7-j 3- [4-hydroxy-4- (2-methoxyphenyl) -l-piperidyl] -

propoxy j - 3,4-dihydrocarbostyrene-monohydrochloride; colorless, powdery crystals (from methanol-water); Mp 239 to 241 ° C.

Example 107

50 4-methyl-j 3- [4- (4-acetyl-4-phenyl-l-piperidyl] propoxy | carbostyril; pale yellow, needle-shaped crystals (from methanol); mp 212 to 213 ° C.

Example 108

1.43 g of l-methyl-6- (2-bromoethoxy) -3,4-dihydrocarbostyrene, 55 1.3 g of 4-acetyl-4-phenylpiperidine and 1 g of triethylamine were mixed with 30 ml of dimethylformamide and the mixture was mixed Heated to 60 to 70 ° C for 5 hours. The reaction mixture obtained was concentrated to dryness under reduced pressure. An aqueous 5% strength 60% sodium hydrogen carbonate solution was added to the residue obtained, and the mixture was stirred. The insolubles were collected by filtration, washed with water, dried and then recrystallized from ethanol-water. 1.3 g of l-methyl-6- [2-acetyl-4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril were obtained in the form of colorless, 65 prismatic crystals, mp. 101 to 103 ° C.

By a method similar to that described in Example 108, the compounds of Examples 109 to 111 were obtained as follows.

Example 109

l-methyl-8- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 103-105 ° C.

Example 110

l-methyl-6- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 115-117 ° C.

Example 111

4-methyl- {3- [4- (4-acetyl-4-phenyl) -1-piperidyl] propoxy} • carbostyril; light yellowish brown, needle-shaped crystals (from methanol); Mp 212-213 ° C.

Example 112

1.65 g of 6-hydroxycarbostyril and 0.75 g of granular potassium hydroxide were mixed with 50 ml of methanol and the mixture was concentrated to dryness under reduced pressure. 50 ml of dimethylformamide were added to the residue obtained and mixed well. Then 2.6 g of l- (3-chloropropyl) -4-acetyl-4-phenylpiperidine were added and the mixture was heated to 50 ° C. for 6 hours with stirring. The reaction mixture was concentrated to dryness under reduced pressure, 20 ml of an aqueous 50% sodium hydrogen carbonate solution were added and the mixture was stirred. The insolubles were collected by filtration and washed with water. After the insoluble materials had dried, they were recrystallized from ethanol. 1.1 g of 6- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] carbostyril were obtained in the form of colorless, prism-like crystals, mp. 192.5 to 194 ° C.

Using a method similar to that described in Example 112, the compounds of Examples 113-123 were obtained as follows.

Example 113

5- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from methanol); Mp 265-266 ° C.

Example 114

7- [3- (4-Hydroxy-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, flake-like crystals (from ethanol); Mp 215 ° C.

Example 115

5- {3- [4-Hydroxy-4- (4-chlorophenyl-l-piperidyl] propoxy} ~ 3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ethanol); mp 189 to 190 ° C.

Example 116

5- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; light yellowish, prism-like crystals (from ethanol); Mp 165 ° C.

Example 117

7- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from isopropanol); Mp 159 to 160 ° C.

Example 118

6- [2- (4-acetyl-4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril; colorless, acicular crystals (from ethanol); Mp 158 to 160 ° C.

Example 119

7-j 3- [4-hydroxy-4- (4-methylphenyl) -1-piperidyl] propoxy j - 3,4-dihydrocarbostyril; colorless, flake-like crystals (from ethanol); Mp 188 to 189 ° C.

23 645 892

Example 120

7-j3- [4-hydroxy-4- (2-methoxyphenyl) -1-piperidyl] propoxy} -3,4-dihydrocarbostyril monohydrochloride; colorless, powdery crystals (from methanol-water); Mp 239 to s 241 ° C.

Example 121

l-methyl-6- [2- (4-acetyl-4-phenyl-l-piperidyl) ethoxy] -3,4-dihydrocarbostyril; colorless, prism-like crystals (from ethanol-water); Mp 101-103 ° C.

10th

Example 122

l-methyl-8- [4- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 103-105 ° C.

15

Example 123

4-methyl-j 3- [4- (4-acetyl-4-phenyl) -1-piperidyl] propoxy} • carbostyril; light yellowish brown, needle-shaped crystals (from methanol); Mp 212-213 ° C.

20th

Example 124

2.0 g of 6- [3- (4-acetyl-4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril and 0.25 g of sodium hydride (50% in oil)

25 were mixed in 30 ml of dimethylformamide and the mixture was stirred for 1 hour. Then 0.7 g of methyl iodide was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 80 ml of saturated sodium chloride solution. The organic layer was

Extracted 30 form and the chloroform layer was washed with water and dried. The chloroform was then removed by distillation and the residue was crystallized with hexane. The crude crystals were recrystallized from ligroin; 1.7 g of l-methyl-6- [3- (4-acetyl-4-phenyl-l-piperidyl) - were obtained

35 propoxy] -3,4-dihydrocarbostyril in the form of colorless, needle-shaped crystals, mp. 115 to 117 ° C.

Using a method similar to that described in Example 124, the compounds of Examples 125 to 127 were obtained as follows.

40 Example 125

l-methyl-8- [3- (4-acetyl-4-phenyl-4-piperidyl) propoxy] -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin); Mp 103-105 ° C.

45 Example 126

l-AHyl-5-j2-hydroxy-3- [4- (4-acetyl-l-phenyl-4-piperidyl] propoxy {-3,4-dihydrocarbostyril; colorless, prism-like crystals (from ligroin-benzene); mp . 141 to 142 ° C.

50 Example 127

l-propargyl-5-j2-hydroxy-3- [4- (4-hydroxy-4-chlorophenyl) -1-piperidyl] propoxy ^ -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin acetone); Mp 132-134 ° C.

55 Example 128

2.9 g of l-allyl-5- (2,3-epoxypropoxy) -3,4-dihydrocarbostyril and 2.3 g of 4-acetyl-4-phenylpiperidine were mixed with 30 ml of methanol and the mixture was refluxed for 3 hours heated.

60 The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of acetone, then a 5% solution of oxalic acid in acetone was added with stirring at room temperature to adjust the pH to 4.5 and allowed to stand. The precipitate formed was collected by filtration and washed with acetone. Recrystallization from ligroin-benzene gave 2.72 g of l-allyl-5-j2-hydroxy-3- [4- (4-acetyl-4-phenyl) -l-piperidyl] propoxy j-3,4-dihydrocarbostyril in the form colorless, prism-like crystals, mp. 141 to 142 ° C.

645 892 24

Using a method similar to that described in Example 128, the compounds of Examples 129 and 130 were obtained as follows.

Example 129

l-propargyl-5-j 2-hydroxy-3- [4- (4-hydroxy-4- (2-chlorophenyl) -5 l-piperidyl] propoxy} -3,4-dihydrocarbostyril; colorless, needle-shaped crystals (from ligroin-benzene-acetone); mp 132 to 134 ° C.

Example 130

10th

4-phenyl-6 - j2-hydroxy-3- [4- (4-hydroxy-4-phenyl) -1-piperidyl] propoxy j-3,4-dihydrocarbostyril; colorless, prism-like crystals (from ethanol-water); Mp 177-178 ° C.

Example 131 15

1.8 g of l-allyl-5-hydroxy-3,4-dihydrocarbostyril and 2.6 g of 4-acetyl-4-phenyl-l- (2,3-epoxypropyl) piperidine were mixed with 30 ml of methanol and the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was in

30 ml of acetone was dissolved, then a 5% solution of oxalic acid in acetone was added with stirring at room temperature to adjust the pH to 4.5 and allowed to stand. The precipitate formed was collected by filtration and washed with acetone and then recrystallized from ligroin-benzene. 2.62 g of l-allyl-5-i2-hydroxy-3- [4- (4-acetyl-4-phenyl) -l-piperidyl] propoxy [-3,4-dihydrocarbostyril in the form of a colorless, powdery substance; Mp 141 to 142 ° C.

Using a method similar to that described in Example 131, the compounds of Examples 132 and 133 were obtained as follows.

Example 132

l-propargyl-5- {2-hydroxy-3 - [[4- [4-hydroxy-4- (2-chlorophenyl] -l-piperidyl]] - propoxy | -3,4-dihydrocarbostyril; colorless, needle-shaped crystals ( from ligroin-benzene-acetone); mp 132 to 134 ° C.

Example 133

4-phenyl-6- {2-hydroxy-3- [4- (4-hydroxy-4-phenyl) piperidyl] propoxy [-3,4-dihydrocarbostyril; colorless, prism-like crystals (from ethanol-water); Mp 177-178 ° C.

M

Claims (30)

645 892 PATENT CLAIMS 1. Carbostyril derivatives of the general formula: H* R3 (1) 10th 15 as well as their acid addition salts, salts with basic compounds and quaternary salts of the formula: + , 6th (le) 20th 25th 30th 35 45 wherein in the formulas R1 represents a hydrogen atom, a lower alkenyl group, a lower alkynyl group or a lower alkyl group which can be substituted by one or more phenyl groups; R2 represents a hydrogen atom, a lower alkyl group or a phenyl group; R3 represents a lower alkyl group substituted by one or more phenyl groups or a phenyl group which may have 1 to 3 substituents from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups; R4 represents a hydrogen atom, a hydroxyl group or a lower alkanoyl group; X represents a halogen atom; Y represents a lower alkylene group which may have one or more hydroxyl groups as a substituent or substituents; R6 represents a lower alkyl group and Q represents a halogen atom; n has the value 0.1 or 2; the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton is a single or double bond, with the proviso that when R3 is a lower alkyl group with one or more phenyl groups as substituents, then R4 represents neither a hydroxyl group nor a lower alkanoyl group. 2. carbostyril derivatives and their salts according to claim 1, wherein R4 represents a hydrogen atom. 3. carbostyril derivatives and their salts according to claim 2, wherein R3 represents a phenyl group or a lower alkyl group substituted by one or more phenyl groups. 4. carbostyril derivatives and their salts according to claim 3, wherein R1 represents a hydrogen atom. 5. carbostyril derivatives and their salts according to claim 3, wherein R3 represents a lower alkyl group which may be substituted by one or more phenyl groups. 6. carbostyril derivatives and their salts according to claim 3, wherein R1 represents a lower alkenyl group or a lower alkynyl group. 7. carbostyril derivatives and their salts according to claim 2, wherein R3 represents a phenyl group which may have 1 to 3 substituents selected from halogen atoms, lower alkyl groups and lower alkoxy groups. 8. carbostyril derivatives and their salts according to claim 7, wherein R1 represents a hydrogen atom. 9. carbostyril derivatives and their salts according to claim 7, wherein R1 represents a lower alkyl group which may be substituted by one or more phenyl groups. 10. Carbostyril derivatives and their salts according to claim 7, wherein R1 represents a lower alkenyl group or a lower alkynyl group. 11. Carbostyril derivatives and their salts according to claim 1, wherein R4 represents a hydroxyl group or a lower alkanoyl group. 12. Carbostyril derivatives and their salts according to claim 11, wherein R1 represents a hydrogen atom. 13. Carbostyril derivatives and their salts according to claim 11, wherein R1 represents a lower alkyl group which can be substituted by one or more phenyl groups. 14. Carbostyril derivatives and their salts according to claim 11, wherein R1 represents a lower alkenyl group or a lower alkynyl group. 15. Carbostyril derivatives and their salts according to one of claims 3, 7 and 11, in which Y represents a lower alkylene group. 16. Carbostyril derivatives and their salts according to one of claims 3, 7 and 11, in which Y represents a lower alkylene group which is substituted by one or more hydroxyl groups. 17. l-methyl-5- [3- (4-benzyl-l-piperidyl) propoxy] -3,4-di-hydrocarbostyril according to claim 1. 18. 7- [3- (4-Benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril according to claim 1. 19. 7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril according to claim 1. 20. l-Benzyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril according to claim 1. 21. l-ethyl-5- [2-hydroxy-3- (4-benzyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril according to claim 1. 22. 7- [2-Hydroxy-3- (4-phenyl-l-piperidyl) propoxy] -3,4-di-hydrocarbostyril according to claim 1. 23. l- (3-phenylpropyl) -7- [3- (4-phenyl-l-piperidyl) propoxy] -3,4-dihydrocarbostyril according to claim 1. 24. Process for the preparation of carbostyril derivatives of the general formula (1) 50 55 60 (1) 65 j in the R1, R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton as defined in claim 1, characterized in that one Compound of the general formula (2) 3rd 645 892 0 - y - x (2) io in the R1, R2, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the above meanings and X1 represents a halogen atom, with a piperidine derivative of the general formula ( 3) (la) ho <. x 'r " in the R1, R2, R3, R4, X, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril-5 skeleton have the meanings given in Claim 1, (3) characterized in that a hydroxycarbostyril compound of the general formula (8) , 2nd in which R3 and R4 have the meanings given above,> o is implemented. 25. Process for the preparation of a carbostyril derivative of the general formula (1) (1) 25th (8th) 30th in the R1, R2, X, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the meaning given above, with an epihalohydrin compound of the general formula (11) / Q \ CH "- CHCHoX- (11) 35 in the R1, R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the meanings given in claim 1, characterized in that a hydroxycarbostyril Compound of the general formula (8) in which X3 represents a halogen atom, converted to an intermediate compound of the general formula (12) (8th) 40 45 ochoz (12) in which R1, R2, X, n and the carbon-carbon bond between the 3 and 4 positions in the carbostyril skeleton have the above meanings, with a piperidyl compound of the general formula (10) in which R1, R2, X, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton 50 have the meanings given above, Z for a group .O OH / x 1 of the formula -CH - CH2 or -CH-CH2X, in which X represents a halogen atom, is that the intermediate compound of the formula (12) is also reacted with a piperidine derivative of the general formula (3) X2 - Y -o < R R- 60 (10) ■ ckj (3) in which R3, R4 and Y have the meanings given above and X2 represents a halogen atom. 26. Process for the preparation of a carbostyril derivative of the general formula (Ia) in which R3 and R4 have the meanings given above, 65 is implemented in order to obtain the carbostyril derivative of the general formula (Ia). 27. Process for the preparation of a carbostyril derivative of the general formula (lc) 645 892 4th in the R1, R2, X, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the meanings given above (lc), with a compound of the general formula (14) - ch2- n r r- .4 (14) 10th in the R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton 15 have the meanings given in Claim 1 and R1 'for a lower alkenyl group, a lower one Alkynyl group or a lower alkyl group, which may have one or more phenyl groups as substituted group (s), characterized in that a compound of the general formula (Ib) in which R3 and R4 have the meanings given above and Z 'for a group of the formula 0 OH / \ i -CH-CH2 or -CH-ch2-X3, in which X3 represents a halogen atom, is reacted, the compound of the general formula (14) being prepared by an epihalohydrin of the general formula (11) / ° \ - 3 CH2 - CHCHgX (11) (lb) in which X3 represents a halogen atom, with a piperidine compound of the general formula (3) 25th / \ R (3) "LA R 3rd 30th (x) n in which R3 and R4 have the meanings given above, has been implemented. 29. Process for the preparation of a carbostyril derivative of the general formula (le) in which R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-positions in the carbostyril skeleton have the meanings given above, with a compound of the general formula (13) 35 R - X (13) in which R1 'has the meaning given above and X4 represents a 40 halogen atom, in order to obtain the compound of the general formula (lc). 28. Process for the preparation of a carbostyril derivative of the general formula (id) 45 OH 1 if U , / R ' r3 (le) och2ckch2 - / xr3 (1d) 50 55 in the R1, R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the meanings given in Claim 1, R6 stands for a lower alkyl group and Q stands for a halogen atom, characterized in that a carbostyril derivative of (1) in the R1, R2, R3, R4, X, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the meanings given in Claim 1, characterized in that a hydroxylcarbostyril compound 6Cf of the general formula (8) (8th) 65 in the R1, R2, R3, R4, X, Y, n and the carbon-carbon bond between the 3- and 4-position in the carbostyril skeleton have the meanings given above, with a compound of the general formula (15) R6Q (15) in which R6 represents a lower alkyl group and Q represents a halogen atom. 30. Antihistamine agent, characterized in that it contains at least one carbostyril derivative according to claim 1 as an active ingredient.